NK cells and CD8+, alphabeta-T cell antigen receptor (TcR)+ T lymphocytes (CTL) are cytotoxic lymphocytes that recognize major histocompatibility complex class I antigens on antigen-presenting cells and other tissues. While CTL express TcR that recognize classical MHC class I molecules bound to peptide antigens, both NK cells and CTL express non-rearranging receptors of the Ly49 (in rodents) or killer cell ig-receptor (KIR) family that also bind to classical MHC class I ligands and either activate or inhibit effector function. Another NK receptor of the C-type lectin-like superfamily, designated NKG2D, is present on essentially all NK cells, CD8+, alphabeta-TcR+ T lymphocytes, and ysigma-TcR+ T cells, unlike KIR and Ly49 that are expressed on minor overlapping subsets of NK cells and only memory T cells. Membrane expression of NKG2D requires its non-covalent association with the signaling adaptor molecule DAP10. The NKG2D-DAP1O complex binds to the human non-classical MHC molecules, MICA and MICB. In humans MICA/B is minimally expressed on normal tissues, but abundantly expressed by transformed cells, including ovarian, breast, cervical, and prostate carcinomas. Mouse homologs of MICA/B have not been identified. The specific aims of this program are: 1) to define the structure and function of the NKG2D-DAPI0 receptor complex and its relationship with other activating and inhibitory NK cell receptors, 2) To determine the role of NKG2D-DAP1 0 receptors in the activation of human and mouse T cells, 3) to identify and characterize a functional NKG2D ligand in mice and 4) to generate NKG2D-deficient mice to determine the physiological role of this receptor in NK cell and CD8+ T cell development and effector function. Given the broad distribution of MICA/B on freshly isolated human tumors, studies of the NKG2D-DAP10 receptor may provide new opportunities for immunotherapeutic intervention in cancer.